Genetic testing in cardiovascular disease Atul K. Sachdev, MD

Transcription

1 Genetic testing in cardiovascular disease Atul K. Sachdev, MD New Horizon Healthcare 1

2 Disclosures Speaker Quest/Cleveland HeartLab

3 9p21 The heart attack gene 9p21 is a region of the genome on the short arm of chromosome 9 Considered the most robust genetic marker of coronary artery disease 1 Two SNPs associated with increased risk for CHD events These two SNPs are highly correlated, with almost complete linkage disequilibrium If one SNP has one mutated allele, it is highly likely the other SNP will have one mutated allele Biology of this region is not well understood Contains elements that control gene transcription (1.) Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol. 2012;32(2):

4 9p21-associated risk and frequency Genotype* Associated Risk Population Frequency 1 Noncarrier Heterozygous Homozygous No increased risk of early MI, AAA, or MI/CHD 25% increased risk MI/CHD 49% increased risk early MI 36% increased risk of AAA 56% increased risk MI/CHD 102% increased risk early MI 74% increased risk of AAA 27% 50% 23% *Genotypes for the rs and rs SNPs Due to high linkage disequilibrium, if one SNP is heterozygous the other is very likely to be heterozygous as well (1.) Ivanova AA, Maksimov VN, Orlov PS, Ivanshchuk DE, Savchenko SV, Voevoda MI. Association of the genetic markers for myocardial infarction with sudden cardiac death. Indian Heart J. 2017;69 Suppl 1:S8-S11

5 9p21-associated risk is comparable to smoking and other accepted risk factors Risk Factor and End Point Heterozygous Carriers Homozygous Carriers 9p21 and early MI fold 2.0-fold Current smoker (vs. nonsmoker) fold 9p21 and AAA fold 1.7-fold 9p21 and CHD / MI fold 1.6-fold LDL-c (per SD increase) 5 HDL-c (per SD decrease)* 5 Age (per 5 years increase) 3 Lp(a) (per 10 mg/dl increase) fold 1.3-fold 1.2-fold 1.1-fold 9p21 risk is independent of conventional risk factors for CAD 1 *derived from a risk ratio of 0.71 per SD decrease Endpoint for all risk factors other than 9p21 in this table is CHD (1.) Holdt LM, Teupser D. Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol. 2012;32(2): (2.) Helgadottir A, Thorleifsson G, Manolescu A et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007;316: (3.) Schaefer EJ, Lamon-Fava S, Jennifer JL, et al. Lipoprotein(a) levels and risk of coronary heart disease in men: The lipid research clinics coronary primary prevention trial. JAMA 1994;27: (4.) Helgadottir A, Thorleifsson G, Magnusson KP et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008;40: (5.) The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:

6 9p21 improves risk assessment Which patients may benefit from the 9p21 risk SNPs test? Patients who are of Caucasian, Chinese, Korean, Japanese, or East Indian descent with a family history of cardiovascular disease or who have traditional risk factors The test may also be useful for risk stratification of those patients with diagnosed cardiovascular disease What does this test add to the risk profile of a patient? This test has clinical utility in identifying those subgroups at higher genetic risk of cardiovascular disease, which may: Allow for early detection and more aggressive monitoring, incorporation of lifestyle/behavioral changes, and treatment Help guide therapy selection Be of utility in family counseling

7 9p21 and population attributable risk (PAR) 9p21 has substantial PAR Although the risk levels associated with 9p21 are similar in magnitude to traditional risk factors, the PAR of 9p21 is substantial due to the high frequency of the risk-associated 9p21 variants Therefore, testing for 9p21 risk variants may have implications for early prevention of disease 1 9p21 and Early MI 2 31% 9p21 and AAA 3 26% 9p21 and CHD/MI 2 21% Population Attributable Risk (1.) Roberts R. A customized genetic approach to the number one killer: coronary artery disease. Curr Opin Cardiol 2008;23: (2.) Helgadottir A, Thorleifsson G, Manolescu A et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007;316: (3.) Helgadottir A, Thorleifsson G, Magnusson KP et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008;40:

8 Jenny (61 y/o WF) Homozygous Positive 9P21 Parameter Value Lp-PLA2 Activity 95 (normal < 75) LDL 229 Sweat 2.3 gallons (estimate)

9 LDL Jenny Homozygous Positive 9P LDL on Pravastatin 40 mg and Ezetimibe 10 mg Daily LDL Target /1/ /1/ /1/ /1/2016 1/1/2017

10 LP-PLA2 Activity Jenny Homozygous Positive 9P LP-PLA2 Activity on Pravastatin/Ezetimibe /1/16 10/1/16 11/1/16 12/1/16 1/1/17 Lp-PLA2 Activity Normal

11 Sweat (in gallons) Jenny Homozygous Positive 9P Dr. Sachdev s Sweat Level (in gallons) Sweat /1/ /1/ /1/ /1/2016 1/1/

12 KIF6 One SNP in the KIF6 gene associated with increased CHD risk and event reduction with statin therapy KIF6 is a member of the kinesin superfamily Mediates the transportation organelles, proteins, and messenger RNA Mutation at the SNP can effect function of the cargo-binding domain Expressed in coronary arteries and vascular cells Li Y, Iakoubova OA, Shiffman D, Devlin JJ, Forrester JS, Superko HR. KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy. Am J Cardiol. 2010;106(7):994-8.

13 KIF6- associated CHD risk Carriers: 55% greater CHD risk independent of other risk factors Risk is reduced with 40mg pravastatin NNT = 10 (PROVE-IT) 40-60% RRR (CARE; WOS) Non Carriers: Risk defined by prevalence and severity of other risk factors Minimal response to statins NNT = 125 (PROVE-IT) 6-20% RRR (CARE; WOS) Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 with Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials. The CARE and WOSCOPS Trials. JACC. 2008;51(4):

14 Atorvastatin reduces events more effectively in KIF6 carriers PROVE-IT-TIMI 22 Trial 40 mg pravastatin vs 80 mg atorvastatin Endpoint of death or major CVD events Double-blind trial of ACS patients N=1,778 Primarily middle-aged men with ACS in stable condition Intensive statin therapy (80 mg atorvastatin) was found to reduce events more effectively in KIF6 carriers than in noncarriers Relative risk reduction was 41% in KIF6 carriers and 6% in noncarriers NNT* was 25 for all patients (on atorvastatin) NNT was 10 for KIF6 carriers with atorvastatin (vs. pravastatin) NNT was 125 for noncarriers Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2008;51(4):

15 Support for KIF6 CARE: Cholesterol and Recurrent Events 1 N=2,715 Secondary prevention in patients with a prior MI 40 mg pravastatin vs placebo WOSCOPS: West of Scotland Coronary Prevention Study 1 N=1,561 Primary prevention 40 mg pravastatin vs placebo ARIC: Atherosclerosis Risk in Communities 2 N=13,907 Population-based observational study; CHD endpoint CHS: Cardiovascular Health Study 3 N=3,849 Population-based observational study; MI endpoint WHS: Women s Health Study 4 N=25,283 Randomized, double-blind, placebo-controlled trial Women > 45 years of age without previous history of CHD risk independent of other risk factors PROVE-IT-TIMI 22 Trial 5 N=1, mg pravastatin vs 80 mg atorvastatin Double-blind trial of ACS patients; death or major CVD event endpoint (1.) Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 with Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials. The CARE and WOSCOPS Trials. JACC. 2008;51(4): (2.) Morrison AC, Bare LA, Chambless LE, et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2007;166(1): (3.) Shiffman D, O'meara ES, Bare LA, et al. Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2008;28(1): (4.) Shiffman D, Chasman DI, Zee RY, et al. A kinesin family member 6 variant is associated with coronary heart disease in the Women's Health Study. J Am Coll Cardiol. (5.)Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2008;51(4): ;51(4):444-8.

16 KIF6 summary and clinical implications KIF6 Genotype Carrier Arg/Arg or Trp/Arg Noncarrier Trp/Trp Associated Risk CHD risk increased up to 55% Treatment Consideration Atorvastatin or pravastatin Population Frequency 1 60% No increased CHD risk -- 50% KIF6 Noncarriers No increased risk of CHD events No significant event reduction from statin therapy KIF6 noncarriers may still have standard risk factors that justify statin therapy Clinicians may want to consider combination therapy with other drugs that have been proven to reduce CHD events. KIF 6 Carriers Carriers are at increased CHD risk Risk can be reduced with statin therapy, independent of LDL-C lowering KIF6 helps clinicians provide patients with information about their CHD risk and individualized response to statin therapy (1.) Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 with Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials. The CARE and WOSCOPS Trials. JACC. 2008;51(4):

17 Sharon (72 y/o WF) Homozygous Negative KIF-6 on Pravastatin 80 mg daily Parameter Value Lp-PLA2 207 (normal < 200) LDL 75 Pulse 140 bpm

18 LDL-C Sharon Homozygous Negative KIF LDL-C on Lovastatin 20 mg Daily /1/2012 4/1/2012 5/1/2012 6/1/2012 7/1/2012 LDL-C Target

19 LP-PLA2 Sharon Homozygous Negative KIF Lp-PLA2 on Lovastatin 20 mg Daily Lp-PLA2 Target Range /1/ /1/ /1/ /1/2016 1/1/2017

20 Pulse Sharon Homozygous Negative KIF Dr. Sachdev s Pulse Rate /1/ /1/ /1/ /1/2016 1/1/2017 Pulse

21 The role of ApoE in lipid metabolism ApoE serves as the ligand to LDL receptors ApoE mediates the hepatic uptake of chylomicron remnants, very-low density lipoprotein, and intermediate density lipoproteins Dose J, Huebbe P, Nebel A, and Rimbach G. APOE genotype and stress response a mini review. Lipids in Health and Disease. 2016;15:121

22 3 ApoE isoforms and their effect on plasma lipids ApoE3 has average affinity for hepatic LDL-receptors (LDL-R) No genotype impact ApoE2 has reduced affinity for LDL-R Associated with slow conversion of IDL to LDL Decreased LDL Elevated triglycerides (TG) ApoE4 has increased affinity for LDL-R and limits HDL-binding Inhibits normal cholesterol clearance process (reverse cholesterol transport or RCT) Elevated total cholesterol, LDL, and TG Decreased HDL Mamotte CD, Sturm M, Foo JI, van Bockxmeer FM, Taylor RR. Comparison of the LDL-receptor binding of VLDL and LDL from ApoE4 and ApoeE3 homozygotes. Am J Physiol. 1999;276:E

23 ApoE-associated CVD risk Genotype 2/2 1% 2/3 10% 2/4 2% Population Frequency 1 CVD Risk Treatment Consideration No increased risk 2 to slightly reduced risk 3 Moderate fat diet (35%) if elevated triglycerides 4 Statin therapy 5 3/3 62% No increased risk 2 Normal dietary modifications 3/4 20% 4/4 5% Increased risk (42%) 2 Very low-fat diet (20%) if elevated LDL- C 6 Statin therapy 7 (1) Eichner JE, Dunn ST, Perveen G et al. Apolipoprotein E polymorphism and cardiovascular disease: A HuGE review. Am J Epidemiol. 2002; 155: (2) Song Y, Stampfer MJ, and Liu S. Meta-analysis: Apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004; 141: (3) Zhang Y, Tang HQ, Peng WJ, Zhang BB, and Liu M. Metaanalysis for the association of apolipoprotein E episilon2/epsilon3/epsilon4 polymorphism with coronary heart disease. Chinese Med J. 2015;218: (4) Moreno J, Perez-Jimenez F, Marin C et al. The effect of dietary fat on LDL size is influenced by apolipoprotein E genotype in healthy subjects. J Nutr. 2004; 134: (5) Ordovas JM, Lopez-Miranda J, Perez- Jimenez F et al. Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy. Atherosclerosis. 1995; 113: (6) Lopez-Miranda J, Ordovas JM, Mata P et al. Effect of apolipoprotein E phenotype on diet-induced lowering of plasma low density lipoprotein cholesterol. J Lipid Res. 1994; 35: (7) Nestel P, Simons L, Barter P et al. A comparative study of the efficacy of simvastatin and gemfibrozil in combined hyperlipoproteinemia: Prediction of response by baseline lipids, apo E genotype, lipoprotein(a) and insulin. Atherosclerosis. 1997; 129:

24 Ricky (38 y/o WM) Apo E 3/4 Drinking Red Wine Daily Parameter Value Lp-PLA2 Activity 93 (normal < 75) LDL 158 LDL-P 1983 Alcohol Intake 1-2 glasses wine/day

25 LDL-C Ricky ApoE 3/4 on No Alcohol LDL-C Without Daily Alcohol /1/2016 7/1/2016 8/1/2016 9/1/ /1/2016 LDL-C Target

26 LDL-P Ricky ApoE 3/4 on No Alcohol 2500 LDL-P Without Daily Alcohol LDL-P Target Range 0 6/1/2016 7/1/2016 8/1/2016 9/1/ /1/2016

27 LP-PLA2 Activity Ricky Apo E 3/4 No Alcohol Lp-PLA2 Activity Without Daily Alcohol /1/2016 7/1/2016 8/1/2016 9/1/ /1/2016 Lp-PLA2 Activity Target Range

28 Other Useful Genetic Tests The Genetic Toolbox 4q25: Atrial Fibrillation Risk IL-1: Heightened Response to Inflammation Haptoglobin: CV Risk in Diabetics LPA Aspirin: CV Risk and Aspirin Response LPA-Intron 25: Independent Risk Factor for CV Disease related to LP(a) And More..

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